An inability to oxygenate blood adequately in the lungs, and an inability of peripheral tissues to extract O2 from blood efficiently contribute to both the morbidity and mortality of acute respiratory failure. These studies aim to extend our understanding of mechanisms which limit both pulmonary and systemic O2 transport in acute respiratory failure. Laboratory studies of peripheral O2 extraction are proposed to (1) clarify effects of bacterial sepsis on O2 extraction; (2) quantify the relative contributions of microembolization, altered vascular reactivity and histotoxic effects to the abnormal relationship between O2 delivery (QO2) and uptake (VO2) in sepsis; (3) determine whether systemic microembolization can interfere with tissue O2 extraction and whether this is reversible; (4) clarify contributions of capillary derecruitment versus capillary O2 extraction limitation in setting the minimum O2 delivery required to maintain aerobic metabolism (QO2c); (5) clarify the value of vasoactive drugs or altered hemoglobin P50 in lowering the minimum QO2 required to maintain VO2. Clinical studies of peripheral O2 extraction will determine (1) whether patients with acute respiratory failure associated with septicemia demonstrate an abnormal relationship between O2 delivery and uptake; (2) whether patients with localized lung injury (aspiration pneumonia) demonstrate the same abnormal O2 extraction capacity. Laboratory studies of pulmonary O2 exchange are proposed to explore mechanisms and potential therapeutic value of new forms of ventilatory management of acute respiratory failure. Specifically I will study (1) effects of continuous flow ventilation (CFV) on efficiency of gas exchange assessed by multiple inert gas elimination in normal animals and experimental models of pulmonary edema or increased bronchomotor tone; (2) the potential value of combining CFV with IPPV in maintaining gas exchange in these models; (3) the value of high frequency ventilation combined with IPPV in maintaining gas exchange in these models. Clinical studies using multiple inert gas elimination will assess (1) advanced stages of ARDS, when edema and shunt have attenuated, but where V/Q inequality may still be present. The reason for sensitivity of arterial PO2 to altered FIO2 in this stage will clarify the respective contributions of V/Q inequality, mixed venous PO2 cardiac output, and sensitivity of the distribution to altered FIO2; (2) effects of aminophylline and increased FIO2 on gas exchange in patients with acute on chronic respiratory failure. Collectively, these studies will provide understanding of mechanisms that contribute to limitations in O2 transport to the mitochondria, from which may arise new insight into potentially therapeutic approaches.